Functional antagonism between Helicobacter pylori CagA and vacuolating toxin VacA in control of the NFAT signaling pathway in gastric epithelial cells

Proc. Natl Acad. Sci. USA 102, 9661–9666 (2005).

Speaker：陳家如                          Time：15:10-16:00, Sep 21, 2005

Commentator：吳俊忠 老師                Place：Room 601

Abstract:

Helicobacter pylori is a Gram-negative bacterium, specialized in the colonization of the human stomach. Virulence factors, such as urease, the cytotoxin-associated antigen CagA, VacA or BabA, might account for the development of different diseases. Chronic infection with cagA-positive H. pylori is associated with the development of atrophic gastritis, peptic ulcers, and gastric adenocarcinoma. CagA is a 120–145 kDa protein with a carboxy-terminal variable region. The cagA gene is located at one end of the cag pathogenicity island (cagPAI), a 40-kb DNA fragment that also encodes molecules constituting the bacterial type IV secretion system. Once injected into the gastric epithelial cells by the type IV secretion system, CagA localizes to the plasma membrane and undergoes tyrosine phosphorylation by multiple members of the Src family kinases. Translocated CagA could disturb cellular functions by physically interacting with and deregulating intracellular signaling transducers through both tyrosine phosphorylation dependent and -independent mechanisms. ¹ To further investigate cellular responses to H. pylori CagA, the authors executed a genome-wide screening of CagA- responsive genes by using DNA microarray and identified nuclear factor of activated T cells (NFAT) transcription factors whose binding sites were overrepresented in the promoter regions of CagA-activated genes. The results showed that CagA activates NFAT transcription factors in gastric epithelial cells by inducing nuclear translocation of cytoplasmic NFAT through the PLCg-Ca²⁺-calcineurin pathway. Activation of NFAT required the EPIYA- containing region of CagA but was independent of CagA phosphorylation. The authors also found that activation of NFAT by CagA is antagonized by the H. pylori VacA toxin.

These findings reveal that the two major H. pylori virulence factors inversely control NFAT activity. Deregulation of NFAT, either positively or negatively, may contribute to cellular dysfunctions that underlie diverged clinical manifestations caused by H. pylori infection.²

References:

1. Masanori Hatakeyama Oncogenic mechanisms of the Helicobacter pylori CagA protein. Nature Reviews Cancer 4, 688-694 (2004).

2. Kazuyuki Yokoyama et al. Functional antagonism between Helicobacter pylori CagA and vacuolating toxin VacA in control of the NFAT signaling pathway in gastric epithelial cells. Proc. Natl Acad. Sci. USA 102, 9661–9666 (2005).